PROJECT SUMMARY/ABSTRACT Understanding the mechanisms by which different cells and tissues sense and respond to different endocrine signals is a critical area of research with profound translational importance. Thyroid hormone (TH) is critical to many aspects of human biology and disease, and although this endocrine factor has been studied for more than a century, the pathways through which it affects morphogenesis remain incompletely understood. One system profoundly affected by TH disruption is the skeleton, and both hyper- and hypothyroidism lead to impaired bone growth. Although not well understood, TH may also alter the morphogenesis of specific bones, which can cause craniofacial abnormalities and deafness. This proposal capitalizes on the unparalleled tractability of the zebrafish system to answer fundamental questions about how TH sculpts specific bones during post-embryonic development, with a particular focus on elements involved in hearing. The work focuses on specific skeletal elements that represent the full diversity of bone developmental origins, testing the hypothesis that TH affects morphogenesis of all types of craniofacial bones. To elucidate the mechanisms by which TH signals are transduced, multiple critical signaling pathways will be tested for responsiveness to chronic and acute TH modulation in different skeletal elements. Further, requirements for these pathways in TH-controlled craniofacial morphogenesis will be assessed. The reagents, workflows and data generated in the scope of this grant will lay the groundwork for multiple future projects, including submission of R01 grants at the intersection of developmental biology, anatomy and endocrinology.